Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors block renal glucose reabsorption and have shown marked cardiac protection in type 2 diabetics, and surprisingly, also in non-diabetics. However, the mechanism by which these drugs improve cardiovascular outcomes is unknown. Metabolic heart disease, which is characterized by cardiac hypertrophy and diastolic dysfunction, is associated with obesity and insulin resistance and leads to adverse cardiovascular outcomes including heart failure with a preserved ejection fraction. A high fat, high sucrose “Western” diet can induce metabolic syndrome, an aggregate of obesity-driven clinical phenotypes including insulin resistance, elevated triglycerides, hypertension, and abnormal cholesterol. Using a mouse model of metabolic syndrome and adult rat ventricular myocytes (ARVMs) in vitro, we aim to determine if the SGLT2 inhibitor Ertugliflozin (ERTU) can prevent metabolic syndrome-induced cardiac pathophysiology and whether ERTU can exert a direct action on cardiomyocytes, a cell type lacking SGLT2. SGLT2 inhibitors have been proposed to act directly on the Sodium-Hydrogen Exchanger 1 (NHE1) and thus could have direct action on cardiomyocytes that may mediate cardioprotective effects. Mice were fed either a control diet (CD) or a high fat high sucrose (HFHS) diet ± ERTU for 16 weeks. Echocardiography was performed and heart weights were obtained. ARVMs were used to assess ERTU’s effect on insulin sensitivity in vitro in a high-palmitate, insulin resistance model, and to test the efficacy of the known NHE1 inhibitor Cariporide (NHEi). A NHE1 activity ammonium chloride pulse assay was performed in HEK293 cells over-expressing either wild-type (WT) or a known NHEi-insensitive point mutant NHE1 ± NHEi or ERTU. In HFHS-fed mice, ERTU attenuated weight gain and restored blood glucose, insulin, hemoglobin A1c, and HOMA-IR to CD levels. HFHS-induced cardiac hypertrophy and diastolic dysfunction were prevented with ERTU. In vitro, high palmitate media decreased insulin stimulated AKT signaling compared to low palmitate media and was rescued by either ERTU or NHEi treatment. ERTU inhibited WT NHE1 activity in HEK293 cells by 67%, whereas activity of the NHEi-insensitive mutant NHE1 was unaffected by ERTU treatment. ERTU prevented the hallmarks of diet-induced metabolic heart disease (cardiac hypertrophy and diastolic dysfunction) in mice. These benefits exceed the expected consequences of glucose control alone. The actions of ERTU on ARVMs in vitro suggest the favorable effects on cardiac structure and function may be due, at least in part, to the direct action of the drug on cardiomyocytes. Furthermore, mutational overexpression studies show that ERTU can directly affect NHE1 in cardiac myocytes. Taken together, this thesis provides evidence that the direct cardioprotective effects of ERTU could be via inhibition of NHE1, a critical modulator of intracellular pH and sodium in the cardiomyocyte, with known implications in the pathophysiology of diabetes and heart failure. / 2022-06-04T00:00:00Z

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13558号 / 論医博第2287号 / 新制||医||1067(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩田 想, 教授 中川 一路, 教授 妹尾 浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM